title: Selective permeabilization of the blood-brain barrier at sites of metastasis.
abstract: BACKGROUND
  Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases.
  
  
  METHODS
  BALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadolinium- diethylenetriaminepentaacetic acid, horseradish peroxidase, or radiolabeled trastuzumab ((111)In-BnDTPA-Tz) was injected intravenously. BBB permeability was assessed in vivo using gadolinium-enhanced T1-weighted magnetic resonance imaging and confirmed histochemically. Brain uptake of (111)In-BnDTPA-Tz was determined using in vivo single photon emission computed tomography/computed tomography. Endothelial expression of TNF receptors was determined immunohistochemically in both mouse and human brain tissue containing metastases. Group differences were analyzed with one-way analysis of variance followed by post hoc tests, Wilcoxon signed rank test, and Kruskal-Wallis with Dunn's multiple comparison test. All statistical tests were two-sided.
  
  
  RESULTS
  Localized expression of TNF receptor 1 (TNFR1) was evident on the vascular endothelium associated with brain metastases. Administration of TNF or LT permeabilized the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect at 6 hours. Metastasis-specific uptake ratio of (111)In-BnDTPA-Tz was also demonstrated after systemic TNF administration vs control (0.147±0.066 vs 0.001±0.001). Human brain metastases displayed a similar TNF receptor profile compared with the mouse model, with predominantly vascular TNFR1 expression.
  
  
  CONCLUSIONS
  These findings describe a new approach to selectively permeabilize the BBB at sites of brain metastases to aid in detection of micrometastases and facilitate tumor-specific access of chemotherapeutic agents. We hypothesize that this permeabilization works primarily though TNFR1 activation and has the potential for clinical translation.
authors.affiliation: Affiliations of authors: CRUK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital, Oxford, UK (JJC, GC, BC, KAV, AH, NRS); Department of Pharmacology (JJC, AH, DCA) and Department of Oncology (JJC, GC, BC, KAV, AH, LS, NRS), University of Oxford, Oxford, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Connell
authors.forename: Grégoire
authors.initials: G
authors.lastname: Chatain
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vallis
authors.forename: Alastair
authors.initials: A
authors.lastname: Hamilton
authors.forename: Len
authors.initials: L
authors.lastname: Seymour
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology; D003287:Contrast Media / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D019786:Gadolinium DTPA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008233:Lymphotoxin-alpha / Q000008:administration & dosage / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D010539:Permeability / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000032:analysis*; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D000068878:Trastuzumab; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003287:Contrast Media; D008233:Lymphotoxin-alpha; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019786:Gadolinium DTPA; D000068878:Trastuzumab